Key result
Rare HDL-C–raising SCARB1 mutations are not associated with coronary artery disease risk.
Why the study?
It was uncertain whether alleles in or near SCARB1 that associate with elevated HDL-C also associate with increased risk of coronary artery disease in a homogeneous population.
Do rare SCARB1 mutations that raise HDL-C associate with increased risk of coronary artery disease in the Icelandic population?
Case-Control (n=343,154)
Do rare SCARB1 mutations that raise HDL-C associate with increased risk of coronary artery disease in the Icelandic population?
Genetically compromised SR-BI function leading to elevated HDL-C is not a marker of increased CAD risk, contradicting previous findings on the p.P376L mutation.
Answers are grounded in this paper and cite their sources.
SCARB1 mutations raising HDL-C do not increase CAD risk; challenges prior reports and leaves open HDL causality in atherosclerosis.
Aims: Scavenger receptor Class B Type 1 (SR-BI) is a major receptor for high-density lipoprotein (HDL) that promotes hepatic uptake of cholesterol from HDL. A rare mutation p.P376L, in the gene encoding SR-BI, SCARB1, was recently reported to associate with elevated HDL cholesterol (HDL-C) and increased risk of coronary artery disease (CAD), suggesting that increased HDL-C caused by SR-BI impairment might be an independent marker of cardiovascular risk. We tested the hypothesis that alleles in or close to SCARB1 that associate with elevated levels of HDL-C also associate with increased risk of CAD in the relatively homogeneous population of Iceland. Methods and results: Using a large resource of whole-genome sequenced Icelanders, we identified thirteen SCARB1 coding mutations that we examined for association with HDL-C (n = 136 672). Three rare SCARB1 mutations, encoding p.G319V, p.V111M, and p.V32M (combined allelic frequency = 0.2%) associate with elevated levels of HDL-C (p.G319V: β = 11.1 mg/dL, P = 8.0 × 10-7; p.V111M: β = 8.3 mg/dL, P = 1.1 × 10-6; p.V32M: β = 10.2 mg/dL, P = 8.1 × 10-4). These mutations do not associate with CAD (36 886 cases/306 268 controls) (odds ratio = 0.90, 95% confidence interval 0.67-1.22, P = 0.49), despite effects on HDL-C comparable to that reported for p.P376L, both in terms of direction and magnitude. Furthermore, HDL-C raising alleles of three common SCARB1 non-coding variants, including one previously unreported (rs61941676-C: β = 1.25 mg/dL, P = 1.7 × 10-18), and of one low frequency coding variant (p.V135I) that independently associate with higher HDL-C, do not confer increased risk of CAD. Conclusion: Elevated HDL-C due to genetically compromised SR-BI function is not a marker of CAD risk.
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Helgadóttir et al. (2018) conducted a case-control in Coronary artery disease (n=343,154). Rare SCARB1 mutations vs. Non-carriers was evaluated on Coronary artery disease (OR 0.90, 95% CI 0.67-1.22, p=0.49). Rare SCARB1 mutations that raise HDL-C levels do not associate with an increased risk of coronary artery disease.
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